1 SUBMITTED 27 JUN 22 1 REVISION REQ. 20 JUL 22; REVISION RECD. 25 JUL 22 2 ACCEPTED 3 AUG 22 3 ONLINE-FIRST: AUGUST 2022 4 DOI: https://doi.org/10.18295/squmj.8.2022.046 5 6 Monkeypox Outbreak 7 More queries posed as cases globally soar 8 *Salah T. Al Awaidy,1 Faryal Khamis,2 Malik Sallam,3 Ramy M. Ghazy,4 9 Hassan Zaraket5 10 11 1Office of Health Affairs, Ministry of Health, Muscat, Oman; 2Adult Infectious Diseases, 12 Department of Medicine, Royal Hospital, Ministry of Health, Muscat, Oman; 3Department of 13 Pathology, Microbiology and Forensic Medicine, School of Medicine, the University of 14 Jordan, Amman, Jordan; 4High Institute of Public Health, Alexandria University, Egypt; 15 5Department of Experimental Pathology, Immunology and Microbiology, American 16 University of Beirut, Lebanon. 17 *Corresponding Author’s e-mail: salah.awaidy@gmail.com 18 19 Introduction 20 Emerging and re-emerging infectious diseases outbreaks are on the rise, with devastating 21 effects on people's health, society, and economy.1 An outbreak of human monkeypox (HMPX) 22 in multiple non-endemic countries has been announced by the World Health Organization 23 (WHO) in early May 2022 with the majority of cases having no confirmed travel to endemic 24 countries.2 The causative agent, monkeypox virus (MPXV), was isolated for the first time in 25 1958 by the Staten’s Serum Institute in Copenhagen, Denmark.3 The virus is classified as a 26 species within the Orthopoxvirus genus together with variola virus, the causative agent of 27 smallpox.4 The MPXV causes similar, albeit less severe clinical manifestations compared to 28 smallpox with lower case-fatality rate (CFR).4 29 30 Monkeypox is considered a zoonotic disease, being transmitted from animals to humans with 31 limited chains of human-to-human transmission.5 The HMPX cases were frequently detected 32 near tropical rainforests, the habitat of a variety of animals known to harbour MPXV.5 33 2 Examples of these animals include squirrels, Gambian rats, dormice, monkeys of various 34 species, among other animals; however, the definitive animal reservoir of MPXV remains 35 unknown.4,5 Prior to the current outbreak in non-endemic countries, HMPX has been endemic 36 in Central and West Africa.4 Occasional outbreaks outside Africa were linked to history of 37 travel or imported animals from endemic regions.4,5 38 39 The HMPX is a contagious infection that leaves a distinctive rash, following exposure via close 40 contact with an infected animal's bodily fluids or through a bite. It can also be acquired through 41 preparation of bush meat or with infectious sores, scabs, or body fluids (in human-to-human 42 transmission), or through respiratory secretions. The incubation period ranges from 5 to 21 43 days.6,7 The prodromal phase, which may not manifest in all cases, resembles influenza illness 44 and includes fever, headache, backache, lymphadenopathy and fatigue.8 Following the 45 prodrome, the affected individuals develop a rash, initially macular that evolves to papules, 46 vesicles then pustules within 1-5 days.6 The skin lesions could be present on the hands, feet, 47 chest, face, genitalia or the anus.6,8 Before healing, the pruritic skin lesions evolve through a 48 number of phases, eventually forming scabs.8 Enanthems could occur as well, involving the 49 mouth, vagina or anus.8 Complications such as sepsis, pneumonia, bacterial super-infection, 50 vision loss, skin scarring, encephalitis, dehydration, skin pigmentation, and death may occur.9 51 The smallpox vaccines used in the past are 85% effective in preventing HMPX, however, its 52 use has ceased since the eradication of smallpox.10 More recently, a novel two-dose vaccine 53 based on the modified attenuated Vaccinia virus was approved. In addition, antivirals such as 54 tecovirimat, which was licensed by the European Medicines Agency (EMA) in 2022, are 55 available, albeit with limited or no human safety and efficacy data.11 56 57 Global burden of HMPX 58 Before the ongoing 2022 HMPX outbreak, a majority of infections that were reported in the 59 endemic regions were caused by animal to human spillover, with rare cases of human-to-human 60 transmission that primarily involved household contacts.7 However, the present epidemic 61 serves as a reminder of how viruses capable of sustained human transmission can emerge 62 suddenly.12 63 64 Until recently, HMPX was limited to West and Central Africa, where the virus can be found 65 in several animal species.5,13 and dominated by two separate clades, one of which is exclusive 66 to the Congo Basin and the other is prevalent in West Africa.4 The Congo Basin lineage is 67 3 expected to be more contagious and has historically been associated with more severe illness 68 and a higher case fatality rate (CFR, 10.6% 95% CI 8.4-13.3%).4, 11 69 It has been confirmed that the West African clade is indeed the clade associated with the 70 current HMPX outbreak and is characterized by a lower CFR (3.6%, 95% CI 1.7 – 6.8%).14 71 An important and urgent call for modification of the MPXV clades’ nomenclature has been 72 advocated to make it non-discriminatory and non-stigmatizing with reliance on Arabic 73 numerals for clade assignment rather than geographic location.15 74 75 The cumulative number of confirmed HMPX cases that have been reported to WHO exceeded 76 3500 and one fatality reported from 50 countries between April and till 27 June 2022.16 These 77 cases were reported in four different WHO regions namely the Region of the Americas, the 78 European, Eastern Mediterranean, and Western Pacific Regions in countries where MPXV is 79 not endemic.16 The vast majority of confirmed HMPX cases were reported from the WHO 80 European Region and the Region of the Americas [Figure 1]. 81 82 The second meeting of WHO held on 23 June 2022, concurred with the International Health 83 Regulations (IHR) Emergency Committee that multi-country monkeypox outbreak does 84 presently constitute a Public Health Emergency of International Concern (PHEIC). The current 85 ongoing HMPX outbreak presents a moderate danger to global public health according to the 86 WHO.2 Contrary to the previous HMPX cases in the endemic regions, no linkages to animals 87 have been traced amid the ongoing outbreak, and the initial cases were reported in Europe, 88 which may hint that the virus could have been circulating between people for months 89 unnoticed.6,18 90 91 Since the first recorded case in April 2022, no fatalities have been recorded so far amid the 92 ongoing outbreak in previously non-endemic countries as a result of the disease.2 Males make 93 up the majority of confirmed cases of monkeypox, and the majority of these cases were among 94 males who have sex with males (MSM) in densely populated metropolitan settings.2 In 95 addition, more cases of HMPX have been recorded in the WHO African Region, where the 96 disease is endemic with 1536 suspected cases since the start of the year 2022, of which 59 cases 97 have been confirmed and 72 fatalities have been recorded.2 Worth mentioning that contrary to 98 the relatively high case fatality rate in Africa, the lack of fatalities in the current outbreak 99 outside Africa could be linked to early detection of cases and quality of health care including 100 the use of antivirals and prophylactic vaccines. 101 4 102 The ongoing detection of the virus and the reported deaths in several African countries 103 underpin the urgent need to better understand the source and the transmission dynamics of the 104 diseases and to provide people with the knowledge and resources they need to safeguard 105 themselves and others in a variety of situations. 106 107 Measures needed to mitigate and stop the spread. 108 The public health hazards of HMPX is on rise, with ongoing transmission of the virus and 109 potential spread to people at higher risk of development of severe illness, such as pregnant 110 women, young children and those with impaired immune systems (immune-compromised 111 individuals), as virus seizes the opportunity to establish itself as a resident human pathogen.19 112 113 In the context of the current multi-country HMPX outbreak, and at this stage, it is vital to 114 establish reliable and efficient surveillance at a national level, since failure to do so raises the 115 risk of undetected cases and uncontrolled spread of the outbreak to additional regions/countries. 116 117 Another issue to be considered is that the majority of cases have been reported among MSM 118 or in healthcare settings. Therefore, the countries are recommended to seek out overlooked 119 cases while conducting contact tracing. Testing and identification of suspected cases are 120 essential to monitor the progress of the outbreak and to direct the vaccination programs. 20 121 122 Moreover, since a majority of emerging infectious disease incidents that afflicted humans in 123 the recent era were zoonotic in nature, the importance of proactive zoonotic and animal 124 surveillance activities should be highlighted.20 125 126 Regarding the utility of smallpox vaccinations for the prevention of HMPX, the WHO released 127 interim recommendations, stating that vaccination should only be used when necessary and 128 does not advocate widespread HMPX immunization.21 To learn more about the effectiveness 129 of vaccines as they are used in the current situation, the countries are required to cooperate in 130 the adoption of standardized research protocols tackling this aim. 131 The WHO endorsed the use of vaccines in the fight against the outbreak. Vaccination of 132 contacts cases, and post-exposure prophylaxis (PEP) including health care workers, 133 researchers dealing with orthopoxviruses, and clinical lab technicians to be provided 134 5 preferably within four days of the initial exposure, in order to avoid the start of illness in 135 these contacts.21 136 In addition to the need of information on HMPX vaccinations and their usage 137 recommendations for exposed individuals, as well as antivirals and the necessity of deploying 138 these vaccines and antivirals where they are required. In January 2022, the European 139 Medicines Agency authorized tecovirimat, an antiviral originally designed to fight 140 monkeypox, for the treatment of monkeypox. In the context of a monkeypox epidemic, there 141 is a limited of experience with these therapies.21 Additionally, it is crucial to improve 142 laboratory and diagnostic capabilities, clinical management, and measures to prevent and 143 control infection in health care and community settings. 144 145 Conclusions and the way forward 146 The rapid transmission of HMPX and its widespread detection in various countries 147 worldwide can be viewed as an emergency of international concern.2 The current multi-148 country outbreak of the disease is evolving, with potential risk of further spread if swift 149 containment interventions are not promptly devised and followed. 150 151 The CFR observed in the African region in contrast to what we are seeing outside of Africa 152 outbreak highlights the need for assistance involving all response components, including but 153 not limited to community awareness-raising, risk communication, human and animal 154 surveillance, diagnostic and laboratory assistance, and regional research and analysis of 155 antivirals and vaccines. This is critical to curb the current outbreak but also prevent future 156 ones at their source. Countries that have recently been impacted by HMPX and those that 157 have experienced it for a long time need vigilant intervention measures. 158 159 To contain MPXV transmission, we call for an urgent action to interrupt the chains of virus 160 spread in non-endemic and endemic countries. A special attention should be focused on 161 ensuring effective surveillance in highly vulnerable groups in terms of exposure or disease 162 severity with cautious approach to avoid potential stigmatization of these groups.22 163 Currently, global and regional public health authorities are recommended to: (1) amend the 164 law to enable it to list HMPX as a notifiable disease; (2) ensure robust surveillance with 165 emphasis of zoonotic disease surveillance in place by all countries, including appropriate 166 contact-tracing, isolation and care of patients; (3) call for immediate involvement by the 167 national advisory committees and panels of scientific experts and groups to formulate the 168 6 roadmap necessary to limit and contain the threat of HMPX. The WHO recommends that 169 potential cases should be reported immediately and investigated within 48 hours; and the 170 health professionals need to be aware and involved in the developing epidemic management 171 framework that has proven successful in other contexts for effective planning and response 172 owing to the nature of disease propagation in an outbreak environment.23 173 174 Without increased and efficient efforts, we run the risk of the progress we have made toward 175 controlling this illness worldwide. Collaborative efforts especially at the national levels are 176 urgently needed worldwide to provide accurate and reliable information about the disease to 177 the general population as well as to most-at-risk group which can help to halt the virus spread. 178 179 Authors’ Contribution 180 SA, FK generated the idea. SA, FK, MS, RG and HZ designed and structured the manuscript. 181 SA, MS, HZ, RG and FK drafted the manuscript. 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Bragazzi NL, Khamisy-Farah R, Tsigalou C, Mahroum N, Converti M. Attaching a 256 stigma to the LGBTQI+ community should be avoided during the monkeypox epidemic. 257 Journal of Medical Virology. 2022/06/02 2022;n/a(n/a), 258 doi:https://doi.org/10.1002/jmv.27913. 259 https://www.who.int/emergencies/disease-outbreak-news/item/2022-DON396 https://www.who.int/news-room/questions-and-answers/item/monkeypox?gclid=CjwKCAjwrNmWBhA4EiwAHbjEQM3ca4RCOhXBks5pD65waOwNH7YVkP4-s9sFMGDwqPbU0iZuQQZKThoCIOgQAvD_BwE https://www.who.int/news-room/questions-and-answers/item/monkeypox?gclid=CjwKCAjwrNmWBhA4EiwAHbjEQM3ca4RCOhXBks5pD65waOwNH7YVkP4-s9sFMGDwqPbU0iZuQQZKThoCIOgQAvD_BwE https://www.who.int/news-room/questions-and-answers/item/monkeypox?gclid=CjwKCAjwrNmWBhA4EiwAHbjEQM3ca4RCOhXBks5pD65waOwNH7YVkP4-s9sFMGDwqPbU0iZuQQZKThoCIOgQAvD_BwE 9 260 Figure 1: The global distribution of human monkeypox (HMPX) cases as of 27 June 2022.17 261